# Control of PGC1alpha Translation and Function

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2020 · $582,181

## Abstract

a. Abstract
The transcriptional coactivator PGC1α was discovered by my group in 1998. It functions as a dominant
regulator of mitochondrial biogenesis and oxidative metabolism by coactivating several nuclear transcription
factors that control the broad program of mitochondrial gene expression. PGC1α also has important tissue
specific functions, including control of adipose thermogenesis, the fasting response in liver, and mitochondrial
biology and resistance to atrophy in skeletal muscle. Mechanisms that activate thermogenesis in fat and
prevent atrophy in muscle are of enormous importance in human metabolic diseases such as diabetes and
obesity. Preliminary data illustrates a very robust and novel translational control of PGC1α mRNA in cultured
cells and in vivo; this mRNA translation is regulated by insulin and IGF1 signaling through AKT and
mTORC signaling. Moreover, it is negatively regulated by the presence of a very small open-reading
frame (uORF) just upstream of the codon that begins translation of the canonical PGC1α1 (the
canonical PGC1α isoform; hereafter just called PGC1α) mRNA. Loss of this uORF by deletion or mutation
increases the translation of PGC1α mRNA while ablating the insulin/IGF1 effect. This uORF encodes a
predicted peptide of 15 amino acids that is strongly conserved in all mammalian species. We will begin these
studies by using several mouse models using CRISPR technology (now created) which increase or decrease
expression of this uORF by altering the start codon of this small encoded peptide (Aim 1). Mice will be
analyzed for effects on key aspects of animal metabolism and physiology (Aim 2). These will include energy
expenditure and resistance to obesity-linked glucose intolerance via thermogenic fat, gluconeogenesis in liver
and exercise tolerance in muscle. Since skeletal muscle and its atrophy is a critical component of aging and an
important target of insulin action, we will examine atrophy in the muscle-selective models. Mechanisms by
which the 5' UTR and uORF control translation of PGC1α mRNA will be examined in cells by determining if the
uORF functions in cis or trans via 2 plasmid experiments and through use of molecular “toeprint” and “footprint”
assays (Aim 3). The presence of the uORF peptide in cell extracts will be determined by Mass Spectrometry
with the use of synthetic “heavy” peptides as key internal standards. Moreover, we will set up an in vitro
translation system and determine if this regulation can be recapitulated in vitro. Key regulatory components of
this system will be isolated by established affinity chromatography methods using oligonucleotides. Finally,
Aim 4 will address the critical question of how insulin/IGF1 signaling impacts this translational control through
quantitative phosphoprotein Mass Spectrometry in insulin treated cells. Phospho-proteomic analyses will also
be applied to components isolated through the affinity methods described above. Together, these data will
provide crucia...

## Key facts

- **NIH application ID:** 9857013
- **Project number:** 5R01DK119117-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** BRUCE M. SPIEGELMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $582,181
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857013

## Citation

> US National Institutes of Health, RePORTER application 9857013, Control of PGC1alpha Translation and Function (5R01DK119117-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857013. Licensed CC0.

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